Q fever is a zoonotic disease of worldwide significance caused by the obligate intracellular bacterium Coxiella burnetii. Due to the highly infectious nature of C. burnetii, its normal route of infection by aerosol, and its hardiness in adverse environmental conditions, the organism has been included in the list likely agents to be used in bioterrorism and biological warfare. Animal models being used to study this disease include mice and guinea pigs infected through intraperitoneal inoculation. Few studies have utilized aerosol infection, and none have evaluated the effect of inhalation dose on clinical disease. Descriptions of the immune response in guinea pigs to Q fever are incomplete, and application of this model for vaccine testing has not been reported. The specific aims for the proposed studies are: 1) Establish the aerosol route of infection in the guinea pig model of Q fever, 2) Characterize the immune response in aerosol-infected guinea pigs, and 3) Determine the nature of protective immunity conferred by recombinant proteins. Guinea pigs will be infected with multiple doses of C.burnetii in a specialized chamber designed to deliver droplet nuclei directly to the alveolar spaces. Each animal's clinical signs, pathologic changes, and immunologic response to infection will be evaluated and correlated with dose. A single disease-causing dose based on these results will be used in vaccine challenge studies. The findings of these studies are of utmost importance in reaching the long-range goal of the development of a safe, effective subunit vaccine for individuals at risk of infection with C. burnetii. The proposed work will provide vital information about this underutilized model for use in current and future vaccine development studies and will allow Dr. Russell the opportunity to develop her scientific career as an independent investigator.